This invention relates to the preparation of derivatives of [[(pyridil substituted)methyl]thio]benzomidazol useful as intermediates in the synthesis of derivatives of [[(pyridil substituted)methyl]sulfinyl]benzomidazol.
Certain derivatives of [[(pyridil substituted)methyl]sulfinyl]benzomidazol, among which are omeprazol, 2-[[3,5-dimethyl-4-methoxy-2-pyridil)methyl]sulfinyl]-5-methoxy-1H-benzomidazol, lansoprazol, 2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridil]methyl]sulfinyl]-1H-benzomidazol, rabeprazol, 2-[[[3-methyl-4-(3-methoxypropoxy)-2-pyridil]methyl]sulfinyl]-1H-benzomidazol, and pantoprazol, 5-difluoromethoxy-2-[[(3,4-dimethoxy-2pyridil)methyl]sulfinyl]-1H-benzomidazol, are anti-ulcerous agents useful in the treatment of stomach and duodenal ulcers, Zollinger-Ellison syndrome and reflux oesophagitis.
One of the key intermediates in the synthesis of said compounds is the derivative of [[(pyridil substituted)methyl]thio]benzimidazole, with the general formula (I) 
where
each of R1, R3 and R4, independently of each other is hydrogen, an alkyl group with 1 to 6 carbon atoms, an alkoxy group with 1 to 6 carbon atoms, or a fluorinated alkoxy group with 1 to 6 carbon atoms, and
R2 is a nitro group, a halogen, an alkoxy group with 1 to 6 carbon atoms, a halogenated alkoxy group with 1 to 6 carbon atoms, or a group xe2x80x94Oxe2x80x94(CH2)nxe2x80x94OR8, where n is an integer between 1 and 6, both inclusive, and R8 represents hydrogen or an alkyl group with 1 to 6 carbon atoms.
Although many methods have been described for obtaining said compounds with the formula (I), one of the most widely used in the one based on coupling a derivative of 2-methylpyridine (II) 
with the corresponding mercaptobenzomidazol (III): 
The literature describes compounds with the formula (II), where X is a halogen, as the intermediates usually chosen to perform this reaction.
The synthesis of compounds with the formula (II) can be effected by several methods, such as:
by a radical halogenation of the corresponding methylpyridine [ES 2036948] using as a chlorination reagent trichloroisocyanuric acid, N-chlorosuccinimide, etc.;
from the suitable hydroximethylpyridine, by substitution of the hydroxyl by a halogen [ES 2036948, EP 174726, ES 2036502] using as reagent for example thyonil chloride;
from the N-oxide of the corresponding 2-methylpyridine, compound with formula (IV) 
Where R1 is hydrogen, R2 is nitro and R3 is methyl, using as a reagent an alkyl or arylsulfonyl chloride, or a carboxylic acid chloride [ES 2060541]; or
based on the N-oxide of the corresponding 2-methylpyridine, compound with the formula (IV), in two stages, using trichloroisocyanuric acid and later addition of sulfur chloride [ES 2036948].
All of the above methods suffer from important drawbacks:
in general, they require a large number of stages, and in some cases they use very irritating reagents, such as acid chlorides that form hydrochloric acid in the process;
the use of derivatives of 2-halomethylpyridines (compound with the formula (II) where X is a halogen), which usually bring about high levels of irritation, such as the derivatives 4-nitro and 4-(2,2,2-trifluoroethoxy) of 2-chloromethyl-3-methylpyridine and 2-chloromethyl-3,5-dimethyl-4-methoxypyridine; and
in the case of the compound with the formula (IV) where R2 is a nitro group, during the preparation of the compounds with formulae (I) and (II) byproducts are formed in which R2 is a halogen, mainly chlorine (as this is the most used derivative), which in the case of low activated pyridines are quite unreactive to nucleophilic substitution in this position. For example, this is the case with omeprazol, where these byproducts are impurities that are difficult to eliminate.
The invention deals with the problem of developing an alternative method of synthesis of derivatives of [[(pyridil substituted)methyl]thio]benzomidazol, with the general formula (I), which are useful as intermediates of derivatives of [[(pyridil substituted)methyl]sulfinyl]benzomidazol.
The solution disclosed by this invention consists of a process with two stages performed consecutively, and optionally in the same reaction medium, comprising the reaction of the corresponding N-oxide of methylpyridine with the anhydride of activated carboxylic acid or sulfonic acid, and the reaction of the intermediate formed with the corresponding mercaptobenzomidazol.
The method disclosed by this invention has the competitive advantage that it significantly reduces the number of synthesis stages, which implies a great increase of industrial interest as it reduces the cost in comparison with most methods described and reduces the levels of residues formed.
In addition, the intermediates formed after reaction of the corresponding N-oxide of methylpyridine with the activated carboxylic acid or sulfonic acid anhydride produce much lower levels, or nearly inexistent levels, of irritation as compared to the compounds of formula (II), where X is a halogen. Furthermore, the method provided by the invention avoids the handling of these intermediates as they can be made to react in the reaction medium itself.
A further competitive advantage is that the formation is prevented of the corresponding derivative 4-chloro of 2-chloromethylpyridine, which is an important impurity in certain cases, such as in the synthesis of omeprazol.
One object of this invention is a method for obtaining derivatives of [[(pyridil substituted)methyl]thio]benzomidazol, with the general formula (I).
A further object of this invention is a method for obtaining derivatives of [[(pyridil substituted)methyl]sulfinyl]benzomidazol, from compounds with the general formula (I) obtained by the method provided in this invention.
An additional object of this invention are intermediates formed by the reaction of the corresponding N-oxide of methylpyridine with the activated carboxylic acid anhydride of sulfonic acid anhydride, useful as intermediates in the synthesis of derivatives of [[(pyridil substituted)methyl]thio]benzomidazol with the general formula (I). The method for obtaining said intermediates is a further object of this invention.
The invention provides a method, hereinafter referred to as the method of the invention, for obtaining derivatives of [[(pyridil substituted)methyl]thio]benzomidazol, with the general formula (I) 
where
each one of R1, R3 and R4, independently of each other, is hydrogen, an alkyl group with 1 to 6 carbon atoms, an alkoxy group with 1 to 6 carbon atoms, or a fluorinated alkoxy group with 1 to 6 carbon atoms, and
R2 is a nitro group, a halogen, preferably chlorine, an alkoxy group with 1 to 6 carbon atoms, a halogenated alkoxy group, preferably fluorine or chlorine, with 1 to 6 carbon atoms, or a group xe2x80x94Oxe2x80x94(CH2)nxe2x80x94OR8, where n is an integer between 1 and 6, both inclusive, and R8 represents hydrogen or an alkyl group with 1 to 6 carbon atoms,
which comprises:
a) reacting an N-oxide of methylpyridine with the general formula (IV) 
xe2x80x83and where R1, R2 and R3 are as described previously;
with (i) an anhydride of activated carboxylic acid with the general formula (R6CO)2O, where R6 is a halogenated alkyl group, or (ii) with an anhydride of sulfonic acid with the general formula (R7SO2)2O, where R7 is an alkyl group, a halogenated alkyl group or an aryl group, optionally substituted with an alkyl group, in an organic solvent, to provide an intermediate with the general formula (V) or the corresponding salt 
where
R1, R2 and R3 are as described previously, and
R5 is OCOR6 or OSO2R7, where R6 and R7 are as described previously; and
b) reacting said intermediate compound with the general formula (V) with a derivative of 2-mercaptobenzomidazol with the general formula (III) 
xe2x80x83where R4 is as defined above,
in the presence of a base in an organic solvent, to give the compound with the general formula (I).
In the sense meant in this description, the term xe2x80x9cfluorinated alkoxy group with 1 to 6 carbon atomsxe2x80x9d means an alkoxy group with 1 to 6 carbon atoms containing one or more fluorine atoms in substitution of one or more hydrogen atoms, such as 2,2,2-trifluoroethoxy or difluoromethoxy. Likewise, a xe2x80x9chalogenated alkoxy group with 1 to 6 carbon atomsxe2x80x9d means an alkoxy group with 1 to 6 carbon atoms containing one or more halogen atoms, preferably fluorine or chlorine, in substitution of on or more hydrogen atoms. Similarly, xe2x80x9chalogenated alkyl groupxe2x80x9d means an alkyl group containing one or ore halogen atoms, preferably fluorine, in substitution of one or more hydrogen atoms.
Stage a) of the method of the invention occurs in an organic solvent, such as a chlorinated solvent or an ether, preferably dichloromethane, 1,2-dichloroethane, chloroform or 1,1,1-trichloroethane, at a temperature between 20xc2x0 C. and 90xc2x0 C., preferably between 60xc2x0 C. and 84xc2x0 C. In a particular realization the activated carboxylic acid anhydride is trifluoroacetic anhydride, while in another he sulfonic acid anhydride is methansulfonic anhydride or toluensulfonic anhydride.
The intermediate with the general formula (V), can be isolated if desired as a salt of the acid corresponding to the anhydride used in the reaction, or it can be made to react in the reaction medium with the derivate of 2-mercaptobenzomidazol (III).
Stage b) of the method of the invention occurs in an organic solvent, such as a chlorinated solvent, an ether or alcohol, preferably dichloromethane, 1,2-dichloroethane, chloroform, 1,1,1-trichloroethane or methanol, at a temperature between 10xc2x0 C. and 40xc2x0 C., in the presence of a base, preferably triethylamine or sodium methoxide. The compound with the general formula (I) obtained can be isolated if desired as a solid, precipitating it in water/alcohol, preferably in a short-chain alcohol or in water/acetone.
The compound with the general formula (I) is useful as an intermediate for the synthesis of derivares of [[(pyridil substituted)methyl]sulfinyl]benzomidazol, among which are compounds with therapeutic activity such as omeprazol, lansoprazol, rabeprazol and pantoprazol. For this the thioether group present in the compound with the general formula (I) is oxidized to a sulfoxide group by conventional means, such as with an oxidizing agent as hydrogen peroxide or sodium percarbonate in the presence of a molybdenum catalyst in a suitable solvent. If the starting point is a compound with the formula (I) where R2 is a nitro group or a halogen, said nitro group or halogen is substituted by the corresponding alkoxy prior to performing the oxidation.
The preferred compounds with formula (I) are those in which R1 is hydrogen or methyl, R2 is nitro, chloro, methoxy, 2,2,2-trifluoroethoxy, 3-methoxypropoxy 3-hydroxypropoxy or 3-chloropropoxy, R3 is methyl or methoxy, and R4 is hydrogen, methoxy or difluoromethoxy.
The compounds with the formula (V) are an additional object of this invention. These compounds may be obtained by reacting the N-oxide of methylpyridine with the formula (IV) with an anhydride of activated carboxylic acid with the general formula (R6CO)2O or with an anhydride of sulfonic acid with the general formula (R7SO2)2O, where R6 and R7 are as described previously, and may be isolated if desired as a salt of the corresponding acid of the anhydride used in the reaction.
The compounds with formula (V) are useful as intermediates in the synthesis of derivatives of [[(pyridil substituted)methyl]thio]benzomidazol with the general formula (I).
In a specific realization the intermediate with the formula (V) is chosen among the group of compounds with formula (V) in which R1 is hydrogen or methyl, R2 is nitro, chloro, methoxy, 2,2,2-trifluoroethoxy, 3-methoxypropoxy, 3-hydroxypropoxy or 3-chloropropoxy, R3 is methyl or methoxy, and R5 is trifluoroacetyloxy, mesiloxy or tosiloxy. In a specific realization, the compound with the formula (V) is a compound with the formula (V) where R1 is hydrogen, R2 is nitro, R3 is methyl and R5 is trifluoroacetyloxy, mesiloxy or tosiloxy. In another realization, the compound with the formula (V) is a compound with the formula (V) where R1 is methyl, R2 is nitro, R3 is methyl and R5 is trifluoroacetyloxy, mesiloxy or tosiloxy. In another specific realization, the compound with the formula (V) is a compound with the formula (V) where R1 is hydrogen, R2 is nitro or chloro, R3 is methoxy and R5 is trifluoroacetyloxy, mesiloxy or tosiloxy.
The following examples are meant for purposes of illustration of the invention and are not meant as a definition of its limits.